1 salivary-gland sporozoites point to tight regulatory control 2 and potential mechanisms for liver-stage differentiation. ABSTRACT 2 8Plasmodium vivax is the key obstacle to malaria elimination in Asia and Latin America, 2 9 largely attributed to its ability to form resilient hypnozoites (sleeper-cells) in the host liver 3 0 that escape treatment and cause relapsing infections. The decision to form hypnozoites is 3 1 made early in the liver infection and may already be set in sporozoites prior to invasion. To 3 2 better understand these early stages of infection, we undertook a comprehensive 3 3 transcriptomic and histone epigenetic characterization of P. vivax sporozoites. The salivary-3 4 gland sporozoite transcriptome is heavily composed of transcripts associated with functions 3 5 needed for early infection of the vertebrate host and development within hepatocytes. 3 6Through comparisons to recently published proteome data for the P. vivax sporozoite, our 3 7 study finds that although highly transcribed, these transcripts are not detectable as proteins 3 8 and may be regulated through translational repression; a finding we test for a small subset of 3 9 transcripts and proteins through immunofluorescent microscopy of sporozoites and liver 4 0 stages in humanized mice. We identify differential transcription between the sporozoite and 4 1 published transcriptomes of asexual blood-stages and mixed versus hypnozoite-enriched liver 4 2 stages. These comparisons point to multiple layers of transcriptional, post-transcriptional and 4 3 post-translational control that appear active in sporozoites and to a lesser extent hypnozoites, 4 4 but largely absent in replicating liver schizonts or mixed blood-stages. Common transcripts 4 5 up-regulated in sporozoites and hypnozoites compared to mixed (i.e., schizont) liver-stages 4 6identify genes linked to dormancy/persistence in bacteria, amoebae and plants. We also 4 7 characterise histone epigenetic modifications in the P. vivax sporozoite and explore their role 4 8 in regulating transcription. Collectively, these data support the hypothesis that the sporozoite 4 9 as a tightly programmed stage primed to infect the human host and identifies potential 5 0 mechanisms for hypnozoite-formation that may be further explored in liver stage models. 5 1 5 2